Project Summary It is well established that obese individuals have increased risks of developing colorectal cancer (CRC), however, the mechanism by which obesity increases the risks of CRC are not well understood and there are few effective strategies to prevent obesity-enhanced CRC. The objective of our research is to determine the roles of soluble epoxide hydroalse (sEH) in obesity-enhanced CRC and to establish an effecitve strategy for prevention of obesity-enhanced CRC using sEH inhibitors that are currently being evaluated in multiple human clinical trials. Our recent publication (PNAS 2018) shows that sEH and its metabolic products are over- expressed in colon of obese mice; in addition, pharmacological inhibition or genetic ablation of sEH abolishes obesity-induced colonic inflammation and activation of pro-tumorigenic Wnt signaling, which are early events involved in the carcinogenesis of CRC and play critical roles in initiation and promotion of CRC. Considering the essential roles of colonic inflammation and Wnt signaling in the carcinogenesis of CRC, in this project we will test our hypothesis that genetic ablation or pharmacological inhibition of soluble epoxide hydrolase (sEH) attenuates obesity-enhanced colorectal cancer (CRC). To test this hypothesis, we propose two specific aims: (1) compare the development of obesity-enhanced azoxymethane (AOM)-induced CRC in sEH-/- and wild-type (WT) mice, and (2) determine the effect of a drug candidate GSK2256294, which is a potent, selective, and reversible sEH inhibitor and has been demonstrated to be safe from human clinical trials, on obesity-enhanced AOM-induced CRC in mice.